Summary The scale of the humanitarian and economic impact of the COVID-19 pandemic places a high priority on the development of prophylactic and therapeutic countermeasures to better control SARS-CoV-2 infections. Among the priorities listed in the NIAID Strategic Plan for COVID-19 research is the need to pursue multiple strategies to develop a COVID-19 vaccine efficacious across the lifespan, including in the elderly. Recent epidemiologic studies have highlighted the potential for Mycobacterium bovis BCG (the only approved vaccine for TB prevention) to mitigate through non-specific immunity the prevalence and severity of the symptoms of COVID-19. Indeed, BCG vaccination has been known since the 1960s to non-specifically improve immunity against a number of viral pathogens resulting in reduced morbidity and mortality in neonates, children and the elderly. Other unique attributes of BCG that make it a vaccine platform of choice for the recombinant expression of heterologous antigens include the fact that it can produce long-lasting CD4+ and CD8+ T cell responses, its natural adjuvant properties, its remarkable safety record (> 5 billion doses given to date) and the fact that it is easy and inexpensive to mass-produce. The goal of this project is to leverage ongoing COVID-19 research efforts at Colorado State University to generate recombinant BCG (rBCG) strains expressing SARS-CoV-2 immunogens (Aim 1) and to assess the immunogenicity and protective efficacy of rBCG in an established animal challenge model of SARS-CoV-2 infection (Aim 2). We hypothesize that the induction of non-specific immunity against SARS-CoV-2 combined with the adaptive immune responses elicited by the recombinant expression of validated SARS-CoV-2 antigens will yield rBCG- based COVID-19 vaccines conferring long-lasting protective immunity in people of all ages. Success in this approach could rapidly deliver an inexpensive, safe and globally deployable vaccine.